Int J Pharm Bio Sci 2015 July; 6(3): (B) 1076 - 1086

Review Article Biotechnology

International Journal of Pharma and Bio Sciences ISSN

0975-6299

REVIEW ON HERPES SIMPLEX VIRUS: CAUSES, AVAILABLE

DRUGS AND FUTURE PROSPECTS
SMRITI SINGH, PRANJIL KULSHRESTHA AND MAYANK AGARWAL*

Department of Biotechnology, Madhav Institute of Technology & Science Gwalior-474005, Madhya Pradesh, India.

ABSTRACT

Herpes simplex virus (HSV-1 and HSV-2) is one of the disease which is found all over the
world. It causes cold sore or watery blisters on the skin and the mucous membrane of
mouth or genitals, and they are contagious and ubiquitous. It can spread with the contact
of the saliva of the infected person. After the primary infection the virus undergoes latent
phase in the cell bodies of neurons which may reactivate if favorable condition is provided.
At present many antiviral drugs were suggested for the treatment of disease and these
have been suggested by many computational and wet lab studies. Drugs like Acyclovir
and other are available in the market for the treatment of HSV but problems like drug
resistance prevent them to provide an efficient and prolong treatment of the disease. In
this study, an analysis of natural and chemical compounds were done which are reported
to inhibit various targets (Proteins) to suppress Herpes Simplex Virus disease.

KEYWORDS: Herpes Simplex Virus, Acyclovir, Neural latency.

MAYANK AGARWAL
*Corresponding author Department of Biotechnology, Madhav Institute of Technology &
Science Gwalior-474005, Madhya Pradesh, India.
mayank0318@gmail.com

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INTRODUCTION
Herpes Simplex Virus Type 1 belongs to the
family Herpesviridae1, subfamily is
Alphaherpesvirinae and genera Simplexvirus2.
It is a linear double stranded DNA virus that can
infect human host naturally1. The herpesvirus
family can be divided into alpha, beta and
gamma subgroups which consist of over 100
double stranded DNA viruses among which
only eight herpesviruses are known to
commonly infect humans3.
Viral structure
There are four components of herpes simplex
virion: double stranded DNA genome (152 kb)4
enclosed in an icosahedral nucleocaspid
surrounded by a proteinaceous tegument and a
lipoprotein envelope5. The DNA core which is
enclosed in icosahedral capsid consist of 162
capsomeres4,6.Out of 11 different glycoproteins
(gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and
gM) at least 8 glycoproteins are involved in
envelop synthesis4.
Mechanism of viral entry into the host cell
There are three phases of Virus-induced
membrane fusion7.The functions of viral
glycoproteins in the fusion process (close
apposition, hemifusion, and complete fusion)
are characterized by the three fusion
process7,8,9.Four membrane glycoprotein (gC,
gD, gB and gHL complex) mediates the fusion
process. Mutants lacking any one of the four
glycoproteins are not infectious as their
replication is blocked at membrane fusion10.The
current model for HSV-1 fusion is that the
required glycoproteins form a fusion
complex11,12, where gC binds a cell surface
receptor (herpesvirus entry mediator, nectin-1,
or modified heparan sulfate), inducing a
conformational change that leads to fusion
mediated by gB and/or gHL12,13. gB and gH are
the most likely candidates to be involved in
Phases II and III of the fusion process.

Figure 1
HSV virion and its two major modes of entry into cell14

Structural components of a typical HSV virion
are shown (box) above (fig. 2)14. HSV particles
initially associate with filopodia-like membrane
protrusions via heparan sulfate proteoglycan
(HSPG). Unidirectional transport of extracellular
particles bound to filopodia (HSV surfing) then
brings the particles closer to the cell body for
entry via interactions with the cellular receptors
including gD receptor and possibly gB receptor.
Fusion at the plasma membrane results in the
release of the naked viral nucleocapsid in the
cytoplasm for transport to the nucleus. Fusion
at the plasma membrane is a pH-independent
process10.

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Figure 2
Molecular interactions that facilitate HSV entry 14

Initial attachment to cells is mediated by
interaction between heparan sulfate
proteoglycans (HSPGs) with HSV glycoproteins
gC and/or gB as shown in (fig 3). Membrane
fusion is required for the penetration of viral
nucleocapsid and the tegument into the
cytoplasm.Glycoprotein gB-gH-gL together
forms the fusion complex. Interaction between
gB, gH-gL and a gD receptor may be sufficient
to bring conformational changes within gD to
trigger merging of viral and cellular membranes
or lipid mixing. However, a fourth glycoprotein,
gB, is also required the release of the tegument
and the nucleocapsid into the cytoplasm14.
Transmission
Symptomatic disease caused by HSV-1 is
typically limited to cold sores of the mouth and
keratitis in the eyes. HSV-2, in contrast, is
mostly responsible for genital lesions. However,
both viruses are capable of causing lesions on
same body sites and both can cause life-
threatening diseases in immunocompromised
individuals including newborns, patients with
human immunodeficiency virus (HIV) or
patients undergoing immunosuppressive
treatment2. Transmission among humans
involves physical contact and often occurs
during kissing (HSV-1) or sexual intercourse
(HSV-2). Herpes simplex viruses can affect
areas of skin exposed to contact with an
infected person. An example of this is herpetic
whitlow which is a herpes infection on the
fingers. This was a common disease of dental
surgeons prior to the routine use of gloves
when conducting treatment on patients. Both
viruses may also be transmitted vertically
during childbirth, although the real risk is very
low15. The risk of infection is minimal if the
mother has no symptoms or exposed blisters
during delivery. The risk is considerable when
the mother gets the virus for the first time
during late pregnancy16. It needs to be
acknowledged that the genital HSV-1 infection
has been common for a long time. For
example, a Japanese study of women,
published in 1976, documented 43% of genital
herpes as caused by HSV-117. In 1977, a
university health clinic study showed that 37%
of women with clinical diagnosis of genital
herpes had HSV-1 isolated18. Among people
with newly acquired genital herpes in Seattle in
the mid to late 1980s, 32% had genital HSV-1
infection 19. Still, several well done studies have
shown that the relative proportion of genital
HSV-1 isolates has increased even more
strikingly in the past two decades20. Two
potential explanations that have been put forth
include a decrease in HSV-1 acquisition among
children, leaving them susceptible to HSV-1 in
adolescence, and increase in oral-genital
contact, or initiation of oral sex instead of
genital-genital sex, among adolescents.
Population based studies, although few have
looked at secular trends in HSV-1 infection, do
not suggest a prominent decrease in HSV-1

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seroprevalence21.Genital herpes is the most
prevalent sexually transmitted disease (STD) in
the United States. The most accurate estimates
derived from seroprevalence surveys show that
1 person in 5 in the United States is infected
with herpes simplex virus (HSV) type 222; these
data are widely purported to estimate the
impact of genital HSV. However, the estimates
ignore the contribution of sexually acquired
HSV-1 to the epidemic of genital herpes.
Infection with HSV-1 usually causes cold
sores23.
Symptoms
Symptoms of herpes simplex virus infection
include watery blisters in the skin or mucous
membranes of the mouth, lips or
genitals24.Lesions heal with a scab
characteristic of herpetic disease. Sometimes,
the viruses cause very mild or atypical
symptoms during outbreaks. However, as
neurotropic and neuro invasive viruses, HSV-1
and -2 persist in the body by becoming latent
and hiding from the immune system in the cell
bodies of neurons. After the initial or primary
infection, some infected people experience
sporadic episodes of viral reactivation or
outbreaks. In an outbreak, the virus in a nerve
cell becomes active and is transported via the
neuron's axon to the skin, where virus
replication and shedding occurs and cause new
sores24.
HSV as a risk factor of Alzheimer’s disease
(AD) and HIV
Although it has a very different course from
Alzheimer’s disease (AD), it leads to the
occurrence of bilateral hippocampal-inner
temporal lesions resulting in profound verbal
memory loss, characteristic of AD25. HSV has
been detected in the brain of many AD patients,
both by direct detection of virus DNA by
polymerase chain reaction (PCR)26 and by the
detection of intrathecal antibodies27.Genital
herpes is a major risk factor for human
immunodeficiency virus type 1 transmission28.
Therapeutics
A number of therapeutics are available against
HSV, of which predominantly include
nucleoside analogues such as triflurothymidine
(TFT), and topical/oral acyclovir. Approximately,
US $17.7 million is expended annually to treat
59,000 new, and 29,000 recurrent, cases of
herpetic eye diseases in the United States. Oral
acyclovir alone costs $8,532 US dollars per
ocular episode averted. If antiviral prophylaxis
were more effective, the cost per infection
would decrease by 51%29. Some drugs
available for treatment of herpes simplex virus
are:

A. Acyclo1vir (Zovirax®)

Figure 3
Showing the structure of Acyclovir (2-Amino-1,9-dihydro-9-
((2-hydroxyethoxy)methyl)-6H-purin-6-one)

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This was the first of a potent new class of inactivates HSV-specified DNA
antiviral agents, licensed in the 1982. It quickly polymerases preventing further viral DNA
replaced vidaribine for use in HSV infection. synthesis without affecting the normal cellular
Available in oral, intravenous and topical (latter processes30, 31, 32.General side effects of drug
form generally not recommended because of include (≥1% of patients) nausea, vomiting,
minimal effectiveness) formulations. DrugBank diarrhea, encephalopathy and headache. If
id-DB00787 have chemical formula C8H11N5O3 administered in high doses can cause
whose molecular massis225.21 g/mol. It has hallucinations. Very rarely it can cause effects
half-life of 2-4 hours and have bioavailability of (<0.1% of patients) like coma,
15-20% available. Aciclovir is converted to seizures, neutropenia, leukopenia, crystalluria,
aciclovir monophosphate by viral thymidine anorexia, fatigue, hepatitis etc33. It is available
kinase, which is then converted by host cell under various brand names like
kinases to aciclovir triphosphate (ACV- Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral
TP)30. ACV-TP, competitively inhibits & , Xovir and Imavir.

B. Valacyclovir (Valtrex®)

Figure 4
Showing the structure of Valacyclovir((S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-
yl)methoxy]ethyl-2-amino-3-methylbutanoate)

Parent compound (prodrug) of Acyclovir that is in phosphorylation of aciclovir than cellular

well absorbed and rapidly metabolized to the thymidine kinase. Subsequently,
active form. It has the advantage of a 3-5x cellular kinases convert the monophosphate
higher bioavailability, thus delivering higher form into active triphosphate form, aciclo-GTP.
levels of active drug with less frequent dosing. Aciclo-GTP is a very potent inhibitor
Its DrugBank id-DB00577 have chemical of viral DNA polymerase and have
formula C13H20N6O4 whose molecular approximately 100 times higher affinity to viral
massis324.336 g/mol. It has a half-life of <30 than cellular polymerase. Its monophosphate
minutes and have bioavailability of 55%. form also incorporates into the viral DNA,
Valaciclovir is an esterified version resulting in chain termination. It has also been
of aciclovir which shows greater oral shown that the viral enzymes cannot remove
bioavailability (about 55%) than aciclovir (10– aciclo-GMP from the chain resulting in inhibition
20%). It is converted by esterases to the active of further activity of DNA polymerase. Aciclo-
drug acyclovir and amino acid valine, GTP is rapidly metabolized within the cell,
via hepatic first-pass metabolism. Aciclovir is possibly by cellular phosphatases34. General
selectively converted into a monophosphate side effects of drug are same as that of
form by viral thymidine kinase, which is much Acyclovir33. It is available under brand name
more effective (3000 times) Valtrex.

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C. Famciclovir (Famvir®)

Figure 5
Showing the structure of Famciclovir (2-[(acetyloxy)methyl]-4-
(2-amino-9H-purin-9-yl)butyl acetate)

Parent compound (prodrug) of penciclovir, a whose molecular massis321.332 g/mol. It has a

newer nucleoside analog which requires
phosphorylation with viral thymidine kinase to
become active (like acyclovir), so cross
resistance occurs. Famciclovir inhibits the viral
thymidine kinase less effectively than acyclovir,
but has higher intracellular levels (good oral
bioavailability) and a longer half-life (18-20h)
than acyclovir, so it is efficacy is similar despite
less frequent dosing intervals. Its DrugBank id-
DB00426 have chemical formula C14H19N5O4
half-life of 2–2.3 hours and have bioavailability
of 75-77% available. During the clinical trials
carried out in 1997 it was found that valaciclovir
was more effective than famciclovir at
suppressing latent viral shedding of Herpes for
long-term treatment35,36,37. Side effects include
mild to extreme stomach upset, headaches,
mild fever. It is available under brand name
Famvir.

D. Foscarnet

Figure 6
Showing the structure of Foscarnet (Phosphonoformic acid)

A phosphate analogue, it inhibits viral DNA CH3O5Pwhose molecular massis126.005

polymerase at the pyrophosphate binding site g/molhave half-life of 3.3-6.8 hours and is
and has little effect on cellular polymerases. administered intravenously only Foscarnet are
Foscarnet does not require phosphorylation to a structural mimic of the
38
become active, so it is effective against the TK- anion pyrophosphate that selectively inhibits
negative strains that are resistant to acyclovir, the pyrophosphate binding site on viral DNA
valacyclovir and famciclovir. It is currently polymerases at concentrations that do not
licensed for the treatment of CMV infections, affect human DNA polymerases. General side
but is also used for therapy of acyclovir- effects include nephrotoxicity,
resistant HSV and VZV as well. Its DrugBank electrolyte disturbances and genital ulceration
id-DB00529 have chemical formula etc.

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Table 1
Current anti HSV drugs and their targets40

Type Drug Target

Guanosine analogs Acyclovir (ACV, Zovirax1) TK, DNA-polymerase, competitive dGTP, chain termination
Valacyclovir (VACV, Valtrex1) TK, DNA-polymerase, competitive dGTP, chain termination
Famciclovir (FCV, Famvir1) TK, DNA-polymerase, competitive dGTP, chain termination
Penciclovir (PCV, TK, DNA-polymerase, competitive dGTP, no chain
Vectavir1/Denavir1) termination
Vidarabine (Ara-A, Arasena A/Vira- TK, DNA-polymerase, competitive dGTP, chain termination
A1)
Pyrimidine analogs Brivudine (BVDU, DNA polymerase, competitive dTTP, no chain termination
Zostex1/Helpin1)
Trifluridine (Viroptic1) DNA polymerase, inhibitor incorporated in both cellular and
viral DNA
Idoxuridine (IDU, DNA polymerase, competitive dTTP
Virunguent1/Stoxil1)
Pyrophosphate Foscarnet (FoscavirTM) DNA polymerase, non-competitive HSV DNA Pol
analog pyrophosphate site
Others Docosanol Viral envelope
Ftibamzone, TDA DNA polymerase

Although acyclovir (a class C medication) is not
FDA-approved for use in pregnancy, numerous
studies have demonstrated its safety during
pregnancy, and the CDC maintained acyclovir
pregnancy registry has failed to show any
increase in fetal anomalies in women who
received acyclovir during the first trimester of
pregnancy39. The newer medications,
valacyclovir and famciclovir, are both class B
medications, but like acyclovir, neither is FDA-
approved for use in pregnancy. Women should
be carefully inspected for lesions immediately
prior to delivery and Cesarian section should be
performed for any woman with typical
prodromal symptoms or lesions consistent with
HSV. Cesarean section, if performed within 4 -
6 hours of membrane rupture, has been shown
to reduce the risk of infection in neonates of
mothers with primary HSV infection 39. Infants
surviving neonatal HSV disease with CNS
involvement had improved neurodevelopmental
outcomes when they received suppressive
therapy with oral acyclovir for 6 months16.
Current strategies to treat HSV infection
A) Computational approach for HSV
treatment
Bioinformatics approach help us to identify
several compounds that can potentially block
the interaction between active residues of gB
and gH-gL complex, suggesting their capability
to inhibit the viral fusion and entry into the host
cell. Compounds like (3-Chloro Phenyl) Methyl-
3,4,5Trihydroxybenzoate(CPMTHB) ,
ZINC01972391 and ZINC04799874 are found
to be common strong inhibitors for both gB and
gH-gL glycoproteins41. Molecular docking study
also shows that the natural antiviral plant
metabolite Geraniin has more affinity for the
thymidine kinase enzyme of HSV-1 as
compared to existing anti-herpes drug
Acyclovir42 and compoundoxoquinoline-
acylhydrazone also shows the anti-herpes
activity43.
B) Natural compounds based study
Natural products generally hold a wide
spectrum of actions against different targets.
This may contribute to low selectivity, but it can
likewise result in comprehensive therapy:
namely, one compound targets several
proteins, several compounds in a plant target
one protein, and/or several herbs target several
proteins. This concept, particularly in traditional
Chinese medicine, is called integrity40. Various
anti-herpes compounds are there which are
categorized into the following classes
1) Terpenoids
Terpenoids with anti-HSV activity includes
monoterpenoids, sesquiterpenoids,

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diterpenoids, iridoids, triterpenoids and

saponins44. 3) Phenols and polyphenols
The phenols were found to have virucidal
2) Flavonoids activity against HSV and delayed the herpes
Flavonoids, such as flavones, flavonols, virus infections. Caffeic acid, obtained from
flavanones, isoflavones, anthocyanidins, Plantago major, exhibited the strongest activity
chalcones and flavanonols, have broad antiviral against HSV-145.
activity. They are abundant in many plant
seeds, citrus fruits, olive oil, tea and red wine40.

Table 2
Table showing the targets of the anti-hsv natural products

Source Compound Target Reference

Myrothamnusflabellifolia Polyphenol fraction Glycoprotein gD 46

Rhododendron ferrugineum Polyphenol fraction Glycoprotein gD 47

Rumexacetosa Polyphenol and flavone fraction Glycoprotein gD 48
Chamaecyparis obtuse Yatein (phenylpropanoid) ICP0 and ICP4 genes 49
Nelumbonucifera Ethanolic extract ICP0 and ICP4 mRNA 50
Curcuma longa Curcumin (polyphenol) P300/CBP histone acetyltransferase 51
Tripterygiumhypoglaucum Alkaloid fraction UL30, UL39 and US6 genes 52
Tethyacrypta Ara-A (nucleoside) Viral DNA polymerase 53,54
Scopariadulcis Scopadulciol (terpene) TK 55
Psychotriaserpens Ethanolic extract TK and ICP27 mRNAs 56

CONCLUSION
There are a variety of natural options available
for the prevention and treatment of
Herpessimplex infections.Although traditional
cell-based screening systems provide ample
opportunities for detecting anti-HSV-1
compounds, its probability is low and the ant
herpetic targets are not named. High
throughput screenings (HTS), especially which
target specific viral proteins are essential for
virus replication, such as helices-primase
complex that represent more efficient means for
discovery of novel drugs with clarified action
mechanisms. The most promising extracts and
fractions of natural materials should undergo
further isolation and refinement steps so as to
distinguish the dynamic ingredients and clarify
the chemical nature and mechanisms of natural
process of these powerful anti-HSV molecules.
Additionally, integrative approaches in chemical
biology have potential to provide important
insight into the mechanism of anti-HSV activity
of the discourses and treat the infection.
Conflict of Interest
Conflict of interest declared none.

REFERENCES

1. Arduino PG, Porter SR. Herpes Simplex
Virus Type 1 infection: overview on
relevant clinico-pathological features. J
Oral Pathol Med 37: 107–121. (2008).
2. Whitley RJ, Roizman B. Herpes simplex
virus infections. Lancet; 357:1513–1518.
(2001). [PubMed:11377626]
3. Shukla D, Spear PG. Herpesviruses and
heparan sulfate: an intimate relationship in
aid of viral entry. J Clin Invest. 108:503–
510. (2001). [PubMed: 11518721]
4. Roizman, B., and A. E. Sears. In B. N.
Fields, D. M. Knipe, and P. M. Howley
(ed.), Herpes simplex viruses and their

This article can be downloaded from www.ijpbs.net

B - 1083
 Int J Pharm Bio Sci 2015 July; 6(3): (B) 1076 - 1086
replication, Fields virology. Lippincott-
Raven, Philadelphia, p. 2231–2295
(1996).
5. Cardone G, Winkler D, Trus D, Cheng N,
John E., Heuser, Newcomb W, Brown J,
and Steven A., Visualization of the Herpes
Simplex Virus Portal in situ by
Cryoelectron Tomography. Virology.10;
361(2): 426–434. (2007).
6. Zhou, Z. H., S. J. Macnab, J. Jakana..
Identification of the sites of interaction
between the scaffold and outer shell in
herpes simplex virus-1 capsids by
difference electron imaging. Proc. Natl.
Acad. Sci. USA 95:2778–2783. (1998)
7. Chernomordik LV, Kozlov MM. Membrane
Hemifusion: Crossing a chasm in two
leaps. Cell, Vol 123:375–382. (2005)
8. Cohen FS, Melikyan GB. Methodology in
the study of cell-cell fusion. Methods
16:215–226. (1998)
9. Blumenthal R, Clague MJ, Durell SR,
Epand RM. Membrane fusion. Chem Rev.
103(1):53-69. 2003.
10. Spear PG. Herpes simplex virus:
receptors and ligands for cell entry. Cell
Microbiol. 2004; 6:401– 410. (2003).
[PubMed: 15056211]
11. Subramanian RP, Dunn JE, Geraghty RJ The
Nectin 1 alpha transmembrane domain, but not
the cytoplasmic tail influences cell fusion
induced by HSV-1 glycoproteins. Virology
339:176–191. (2005).
12. Cocchi F, Fusco D, Menotti L, Gianni T,
Eisenberg RJ, Cohen GH, Campadelli-
Fiume G. The soluble ectomembrane of
herpes simplex virus gD contains a
membrane- proximal pro-fusion domain
and suffices to mediate viral entry,Proc
Natl AcadSci USA, 101:7445–
7450,(2004).
13. Zago A, Jogger CR, Spear PG). Use of
herpes simplex virus and Pseudorabies
virus chimeric glycoprotein D molecules to
identify regions critical for membrane
fusion. Proc Natl AcadSci USA
101:17498–17503. (2004).
14. Akhtar J and ShuklaD.Viral entry
mechanisms: cellular and viral mediators
This article can be downloaded from www.ijpbs.net
B - 1084
of herpes simplex virus entry. FEBS J.
276(24): 7228–7236.(2007).
15. Corey L, Wald A.Maternal and Neonatal
HSV Infections. New England Journal of
Medicine 361 (14): 1376-85. Doi:
10.1056/NEJMra0807633. (2009). PMC
2780322.PMID 19797284.
16. Kimberlin D, Whitley R, Wan W, Powell D,
Storch G, Ahmed A, Palmer A, Sánchez
P. Oral Acyclovir Suppression and
Neurodevelopment after Neonatal Herpes.
N Engl J Med; 365(14): 1284–1292.
(2012).
17. Haddow LJ, Dave B, MindelA. Increase in
rates of herpes simplex virus type 1 as a
cause of anogenital herpes in western
Sydney, Australia, between (2003). Sex
Transm Infect; 82:255–9.(2006)
18. Kalinyak J, Fleagle G, Docherty J.
Incidence and distribution of herpes
simplex virus types 1 and 2 from genital
lesions in college women. J Med
Virol;1:175–81. (1977).
19. Wald A, Benedetti J, Davis G. A
randomized, double-blind, comparative
trial comparing high and standard dose
oral acyclovir for first-episode genital
herpes infections. Antimicrob Agents
Chemother; 38:174–6.(1994)
20. Vyse AJ, Gay NJ, Slomka MJ. The burden
of infection with HSV-1 and HSV-2 in
England and Wales: implications for the
changing epidemiology of genital herpes.
Sex Transm Infect; 76:183–7. (2000).
21. Schillinger JA, Xu F, Sternberg MR.
National seroprevalence and trends in
herpes simplex virus type 1 in the United
States, Sex Transm Dis 2004; 31:753–60.
(1976).
22. Fleming DT, McQuillan GM, Johnson RE.
Herpes simplex virus type 2 in the United
States, N Engl J Med 1997; 337:1105–
11.(1976)
23. Lafferty WE, Coombs RW, Benedetti J,
Critchlow C, Corey L.Recurrences after
oral and genital herpes simplex virus
infection: influence of anatomic site and
viral type. NEngl J Med; 316:1444–9.
(1987)
 Int J Pharm Bio Sci 2015 July; 6(3): (B) 1076 - 1086
24. Ryan KJ, Ray CG., (4th ed.) Sherris
Medical Microbiology. McGraw Hill. ISBN
0-8385-8529-9. pp. 555–62 (2004)
25. Pyles R. The association of Herpes
Simplex Virus and Alzheimer’s disease: a
potential synthesis of genetic and
environmental factors. Herpes 8: 64–68.
(2001)
26. Itzhaki R, Lin WR, Shang D, Wilcock G,
Faragher B, et al. Herpes simplex virus
type 1 in brain and risk of Alzheimer’s
disease. Lancet 349:241–244. (1997)
27. Wozniack M, Shipley S, Combrinck M,
Wilcock G, Itzhaki R. Productive Herpes
simplex virus in brain of elderly normal
subjects and Alzheimer’s disease patients.
J Med Virol 75: 300–306. (2005)
28. David M. Koelle and Lawrence Corey.
Recent Progress in Herpes Simplex Virus
Immunobiology and Vaccine Research.
ClinMicrobiol Rev. Jan; 16(1): 96–
113.doi: 10.1128/CMR.16.1.96-113.2003.
(2003)
29. Lairson, D.R.; Begley, C.E.; Reynolds,
T.F.; Wilhelmus, K.R. Prevention of
herpes simplex virus eye disease: A cost-
effectiveness analysis. Arch. Ophthalmol.,
Vo121, 108–112.
30. "PRODUCT INFORMATION NAME OF
THE DRUG OZVIR
TABLETS" (PDF).TGA eBusiness
Services. Ranbaxy Australia Pty Ltd. 26
August 2011.
31. "Acyclovir (acyclovir) Capsule Acyclovir
(acyclovir) Tablet [Genpharm
Inc.]". DailyMed. Genpharm Inc.
November 2006.
32. "Aciclovir Tablets BP 400mg - Summary
of Product Characteristics
(SPC)". electronic Medicines
Compendium. Actavis UK Ltd. 20 August
2012.
33. Rossi, S, ed. (2013). Australian Medicines
Handbook (2013 ed.). Adelaide: The
Australian Medicines Handbook Unit
Trust. ISBN 978-0-9805790-9-3.
34. http://www.uscnk.us/protein-antibody-
elisa/Valaciclovir-%28VCV%29-V511.htm
35. Comparative efficacy of famciclovir and
valacyclovir for suppression of recurrent
This article can be downloaded from www.ijpbs.net
B - 1085
genital herpes and viral shedding.
Sexually Transmitted Diseases (Vol 33,
page529Another Case of Attempted
Research Suppression: the Famvir vs
Valtrex Study )
36. Another Case of Attempted Research
Suppression: the Famvir vs Valtrex
Study [5]
37. Fife KH. Sexually Transmitted Diseases
Sep;33(9):534-5. (2006).
38. Meyer PR, Rutvisuttinunt W, Matsuura
SE, So AG, Scott WA "Stable complexes
formed by HIV-1 reverse transcriptase at
distinct positions on the primer-template
controlled by binding deoxynucleoside
triphosphates or foscarnet". J. Mol.
Biol. 369 (1):pg.41-
54.doi:10.1016/j.jmb.2007.03.006. PMC 1
986715.PMID 17400246 (May 2007).
39. Prober CG. (1992). “The Management of
Pregnancies Complicated by Genital
Infections with Herpes Simplex Virus,”
ClinInf Dis, (15) 1031-8. (2003)
40. Mei-Gong Zhong, ab Yang-Fei Xiang, ab
Xian-XiuQiu,abZhong Liu, a KaioKitazatoc
and Yi-FeiWanga. Natural products as a
source of anti-herpes simplex virus
agents. DOI: 10.1039/c2ra21464d. (2012).
41. Syed Hussain Basha, DeepthiTalluri and
Nalini Prasad Raminni. Computational
repositioning of ethno medicine elucidated
gB-gH-gL complex as novel anti herpes
drug target. BMC Complementary and
Alternative Medicine 2013, 13:85 (2013)
42. Padmaja Kamath and Ashwani Sharma
Alternative Medicine against Herpes
Simplex Virus Type-1(HSV-1) via
molecular docking. International
Conference & Workshop on Recent
Trends in Technology, (TCET)
Proceedings published in International
Journal of Computer Applications®
(IJCA), Pages 5-11. (2012)
43. JullianeDinizYoneda,MagalyGirão.
Albuquerque et al. Docking of anti-HIV-1
oxoquinoline-acylhydrazone derivatives as
potential HSV-1 DNA polymerase
inhibitors. Journal of Molecular Structure.
Volume 1074, Pages 263–270.(2014)
 Int J Pharm Bio Sci 2015 July; 6(3): (B) 1076 - 1086

44. S. Szostek, B. Zawilinska, J. Kopec and
M. Kosz-Vnenchak, ActaBiochim Pol,Vol
56, pg. 337–342. (2009)
45. A. Greco, J. J. Diaz, D. Thouvenot and F.
Morfin, Infect. Disord.: Drug Targets, ,Vol
7, pg. 11–18. (2007)
46. K. Gescher, J. Kuhn, E. Lorentzen, W.
Hafezi, A. Derksen, A.Deters and A.
Hensel, J. Ethnopharmacol.,Vol. 134, pg.
468–474. (2011)
47. K. Gescher, J. Kuhn, W. Hafezi, A. Louis,
A. Derksen, A. Deters,E. Lorentzenand A.
Hensel, Fitoterapia, Vol 82, pg. 408–413.
(2011)
48. K. Gescher, A. Hensel, W. Hafezi, A.
Derksenand J. Kuhn. Antiviral Res., vol
89, pg. 9–18. (2011)
49. Y. C. Kuo, Y. H. Kuo, Y. L. Lin and W. J.
Tsai, Antiviral Res.,Vol 70, pg.112–
120.(2006)
50. Y. C. Kuo, Y. L. Lin, C. P. Liu and W. J.
Tsai, J. Biomed. Sci., Vol 12, pg 1021–
1034.(2005)
51. S. B. Kutluay, J. Doroghazi, M. E. Roemer
and S. J. Triezenberg, Virology, Vol 373,
pg. 239–247. (2008)
52. Z. Ren, C. H. Zhang, L. J. Wang, Y. X.
Cui, R. B. Qi, C. R. Yang, Y. J. Zhang, X.
Y. Wei, D. X. Lu and Y. F. Wang. Virol.
Sin,Vol 25,pg. 107–114. (2010)
53. W. Bergmann and R. J. Feeney, J. Org.
Chem.,pg. 981–987. (1951)
54. R. J. Whitley, L. T. Chien, R. Dolin, G. J.
Galasso and C. A. Jr. Alford, N. Engl. J.
Med., Vol 294, 1193–1199. (1976)
55. T. Hayashi, Yakugaku Zasshi,Vol 128,pg.
61–79. (2008)
56. Y. C. Kuo, C. C. Chen, W. J. Tsai and Y.
H. Ho, Antiviral Res., Vol 51, pg. 95–109.
(2001).

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